Type 2 Diabetes and Cardiovascular Disease: Reducing the Risk

BACKGROUND: Type 2 diabetes (T2DM) is a major risk factor for developing cardiovascular disease (CVD). The growing epidemic of T2DM has contributed to CVD becoming the leading cause of morbidity and mortality in the United States. OBJECTIVES: To review the pathophysiology of CVD; to demonstrate the interrelatedness of CVD, the metabolic syndrome, and T2DM; and to discuss treatment options that may reduce the risk of CVD in patients with T2DM. SUMMARY: Recent data from the International Diabetes Federation show that the worldwide prevalence of T2DM is much higher than previously estimated. Managing patients with T2DM continues to severely burden the U.S. health care system. Furthermore, most costs associated with managing these patients are associated with treating CVD complications. Studies have shown that several agents can decrease the risk of CVD in patients with T2DM. CONCLUSIONS: To combat the diabetes epidemic, clinicians should treat patients with T2DM and prediabetes early and aggressively to control their metabolic disturbances and reduce the risk of CVD. Diet, exercise, and several pharmacologic agents have been shown to reduce the risk of CVD.

1. Disclose the principal sources of funding in a manner that permits easy recognition by the reader. 2. Disclose the existence of all potential conflicts of interest among supplement contributors, including financial or personal bias. 3. Describe all drugs by generic name unless the use of the brand name is necessary to reduce the opportunity for confusion among readers. 4. Strive to report subjects of current interest to managed care pharmacists and other managed care professionals. 5. Seek and publish content that does not duplicate content in the Journal of Managed Care Pharmacy. 6. Subject all supplements to expert peer review. *A total of 0.20 CEUs (2.0 contact hours) for pharmacists (ACPE Program No. 221-000-07-003-H01) and a maximum of 2.0 AMA PRA Category 1 credits for physicians will be awarded for successful completion of this continuing education program. For faculty disclosures, please see page S13. For accreditation information, please see page S16.
The article published in this supplement represents the opinions of the authors and does not reflect the official policy or views of the Academy of Managed Care Pharmacy, the authors' institutions, Takeda Pharmaceuticals North America, Inc., the National Association of Managed Care Physicians, or ProCE, Inc. Portions of this supplement may include the use or potential use of drugs for unlabeled indications. Before prescribing or making recommendations regarding any medication, clinicians should consult primary references and full prescribing information.

Target Audience
Pharmacists and physicians managing diabetic and prediabetic patient populations

Learning Objectives
Upon completion of this program, participants will be better able to T ype 2 diabetes mellitus (T2DM) has reached the point of a global epidemic. According to newly released data from the International Diabetes Federation (IDF), 246 million people worldwide (5.9% of the world' s adult population) have diabetes and 46% of those affected are 40 to 59 years old. 1 Previous figures from the World Health Organization (WHO) estimated that approximately 171 million people had diabetes. 2 In 2005, estimates from the Centers for Disease Control and Prevention indicated that approximately 7% of the U.S. population, or 20.8 million people, had diabetes. 3 T2DM accounts for 90% to 95% of all diagnosed cases and is usually associated with obesity, physical inactivity, older age, family history of diabetes, impaired glucose metabolism, and history of gestational diabetes. In addition, certain ethnic backgrounds have a higher prevalence of diabetes (African Americans, Hispanic/Latino Americans, American Indians, some Asian Americans, and native Hawaiians or other Pacific Islanders). 3 Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. 4 T2DM diabetes is a major risk factor for developing macrovascular complications, including atherosclerosis, myocardial infarction (MI), stroke, and peripheral vascular disease. In adults with diabetes, the risk of death from heart disease and stroke is 2 to 4 times higher than in adults without diabetes. 3 Furthermore, heart disease and stroke account for approximately 65% of deaths in people with diabetes. 3 Because of the increasing prevalence of diabetes and the complexities of treating patients with multiple comorbidities, costs for T2DM are skyrocketing. Diabetes has become a major cause of morbidity and mortality and is a costly burden on the U.S. health care system. In 2002, the American Diabetes Association (ADA) estimated the total costs (medical expenditures and lost productivity) of diabetes at $132 billion ($92 billion in direct costs and $40 billion in indirect costs). 5 Cardiovascular (CV) complications account for more than 50% of the total costs of managing diabetes complications. It is estimated that the costs for managing complications over a 30-year period are $47,240 per patient. 6 Over this period, approximately $24,330 (52%) is spent on managing macrovascular complications. 6 However, most of these costs occur very early in the progression of T2DM. During the first 5 years of treating patients with T2DM, 85% of the total costs of care are associated with managing macrovascular complications. 6 Over the course of 10 years, management of macrovascular complications remains a significant contributor at 77% of the total cost of care. 6 Consequently, minimizing CV complications with aggressive treatment in the early stages of T2DM may have a significant impact on decreasing health care system costs.

s ss s Metabolic Syndrome
The growing epidemic of obesity in the United States is a major Type 2 Diabetes and Cardiovascular Disease: Reducing the Risk contributing factor to the increased morbidity and mortality associated with T2DM. Approximately 127 million adults in the United States are overweight (body mass index [BMI] 25-29 kg/m 2 ), 60 million are obese (BMI 30-39 kg/m 2 ), and 9 million are morbidly obese (BMI >40 kg/m 2 ). 7 Approximately 90% of patients with T2DM are classified as obese. 7 Obese patients are prone to develop CVD, including chronic venous insufficiency, hypertension, hyperlipidemia, atherosclerosis, stroke, deep vein thrombosis, and peripheral vascular disease. 7 Furthermore, abdominal obesity has been clearly implicated in the development of insulin resistance and the pathogenesis of T2DM and is considered a significant component of the metabolic syndrome. [8][9][10][11][12] The metabolic syndrome has been described by several medical organizations as a cluster of metabolic abnormalities, including insulin resistance, hyperglycemia, hypertension, reduced highdensity lipoprotein cholesterol (HDL-C) levels, and increased triglyceride (TG) levels. 8 Table 1 lists specific definitions of the metabolic syndrome from major medical organizations. 8,[13][14][15][16][17] However, in the United States, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition is generally applied. It is hypothesized that genetic factors predispose the patient to developing the metabolic syndrome, along with acquired factors such as obesity, physical inactivity, and highcarbohydrate diets. 8 Approximately 86% of patients with T2DM have the metabolic syndrome. 18 More important, the prevalence of CVD markedly increases in patients who have this syndrome. 18 Furthermore, the IDF strongly suggests that the metabolic syndrome is the driving force behind the global epidemics of T2DM and CVD. 17

s ss s Pathogenesis of Cardiovascular Disease
Clustered metabolic disorders (hyperglycemia, dyslipidemia, and hypertension), that is, the metabolic syndrome, contribute to the development and progression of CVD. Genetic susceptibility and environmental factors, including poor nutrition, obesity, and lack of physical activity, also play a significant role in developing CVD. [19][20][21][22] Mature adipocytes produce several adipokines (proinflammatory mediators), including C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha (α), visfatin, leptin, resistin, angiotensinogen, and plasminogen activator inhibitor-1 (PAI-1), that are associated with developing CVD. 23 Research has shown that circulating levels of several adipokines are elevated in obese and insulin-resistant states. Additionally, visceral fat appears to secrete higher levels of adipokines than subcutaneous fat. Figure 1 shows how visceral fat accumulation contributes to the metabolic syndrome and leads to the dysregulation of certain adipokines. 24 Loss of visceral fat is associated with decreased circulating levels of most adipokines, but increased levels of adiponectin. 23 Reseachers have found that adiponectin has antiatherogenic properties, whereas other adipokines have atherogenic properties. Furthermore, emerging evidence suggests that certain adipokines may directly affect the endothelium and the progression of atherosclerosis through proinflammatory properties. 23 Endothelial dysfunction is one of the earliest events in the pathogenesis of CVD. 25 The endothelium, the innermost layer of blood vessels, is an active organ that regulates multiple vascular functions. It not only acts as a barrier but also regulates vascular growth, platelet function, and coagulation. When the endothelium is healthy, it releases nitric oxide (NO) and maintains a balance between various functions such as dilatation/constriction, growth inhibition/promotion, antithrombosis/prothrombosis, and anti-inflammation/proinflammation. Under certain conditions (e.g., elevated or oxidated low-density lipoprotein cholesterol [LDL-C], diabetes, hypertension) NO is reduced, leading to imbalance of 1 or more of these functions and a proatherogenic state. 26 The compensatory responses that alter the normal homeostatic properties of the endothelium are key in the development of atherosclerosis.
The proinflammatory state has been directly linked to insulin resistance and atherogenesis. 8 Studies have shown that CRP is a strong predictor of cardiovascular events. 23 Elevated CRP levels are found in obese patients and in those with the metabolic syndrome and are directly correlated with the amount of body fat as assessed by BMI and high waist circumference. CRP decreases NO production and directly influences atherogenesis by inducing the expression of adhesion molecules and leukocyte mediators, which promote adherence to the endothelium. 23 Insulin resistance and several other factors related to central adiposity have been implicated in endothelial dysfunction. Hyperglycemia induces free radical production and increases superoxide production and oxidative stress, which contributes to atherogenesis. Hyperglycemia also augments the expression of adipokines, further inducing adipokine-related endothelial dysfunction. 23 Additionally, impaired insulin action in adipose tissue results in elevated rates of lipolysis and free fatty acid (FFA) release. 23 The increased availability of FFAs leads to several detrimental metabolic effects, including impaired insulin secretion; insulin resistance; impaired vasodilation; reduced NO production; increased levels of small, dense, highly atherogenic LDL-C; and decreased HDL-C levels.
Emerging data continue to support the proposal that abdominal obesity increases CVD risk via production of adipokines, which appear to play a central role and may serve as the cellular link mediating both the metabolic syndrome of insulin resistance and the endothelial dysfunction present in the obese state. 26 Treatment that is focused on reducing total body and visceral fat may help reverse the metabolic and vascular abnormalities. Studies have shown that lifestyle interventions resulting in weight loss and increased physical activity lead to decreased inflammatory proteins and reduced insulin resistance. Several drugs also can reduce inflammatory adipokines. These agents include thiazolidinediones (TZDs), statins, fibrates, niacin, aspirin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). 23 www.amcp.org Vol. 13  ≥126 mg/dL. • Two-hour postload glucose ≥200 mg/dL during an oral glucose challenge (not recommended for routine clinical use). 27 As an adjunct to drug therapy, it is equally important for patients to include lifestyle changes. The ADA released a consensus statement in June 2006 that provided specific recommendations about the type and amount of physical activity needed to achieve CV risk reduction benefits. 28 These recommendations state that 150 minutes per week of moderate-intensity aerobic exercise and/or 90 minutes per week of vigorous aerobic exercise will help improve glycemic control, facilitate weight loss, and reduce the risk of CVD. However, lifestyle changes are often inadequate. Accordingly, the recent consensus statement from the ADA and the European Association for the Study of Diabetes (EASD) recommends initiating drug therapy immediately and in a stepwise approach when treating patients with T2DM. The following interventions are recommended: • Step 1: Initiate metformin (if no contraindications) and lifestyle changes to decrease weight and increase physical activity. • Step 2: Add other therapy, including TZDs, sufonylureas, and/ or basal insulin, to meet glycemic goals. 29 Additional agents that may be used include α-glucosidase inhibitors, meglitinides, pramlintide (amylin analog), exenatide (glucagon-like peptide [GLP-1] receptor agonist), and sitigliptin (dipeptidyl peptidase-IV [DPP-IV] inhibitor). The ADA' s and the EASD' s T2DM treatment algorithm ( Figure 2), based on clinical trials and experience, considers individual therapies, synergistic effects of therapies, and cost of treatments. 29 When treating T2DM, patients may initially be controlled with monotherapy but because of the progressive nature of the disease will eventually require a combination of agents to meet glycemic goals. 29 Table 2 provides a comparison of currently available T2DM oral treatment options. [29][30][31][32] To minimize complications, management of diabetes has increasingly become more aggressive. The recent consensus statement from the ADA and EASD recommends initiating or changing therapy when the glycosylated hemoglobin (A1C) is 7% or greater. 29 Since research has shown the interrelationships among the components associated with T2DM (hypertension, dyslipidemia, hyperglycemia/insulin resistance, and obesity), a multifactorial treatment approach is key to facilitate addressing all metabolic disturbances concomitantly.

Definitions of Metabolic Syndrome From Major Organizations
Because of the increasing number of patients developing T2DM and the impact on CV complications and health care costs, the ADA has undertaken a more proactive approach to help control this epidemic. The ADA' s recent position statement discusses specific nutrition recommendations and other interventions to prevent the onset of T2DM. This statement recommends moderate weight loss (5%-7%), decreased caloric and fat intake (by approximately 30%), and regular physical activity for primary prevention in patients at high risk for developing diabetes. 33 Several studies have shown the benefits of lifestyle changes, such as diet and exercise, in patients with impaired glucose tolerance. [34][35][36] Diet, exercise, and diet plus exercise interventions were associated with 31% (P <0.030), 46% (P <0.0005), and 42% (P <0.005) reductions, respectively, in the risk of developing T2DM, 34 whereas a second study with more intensive individualized diet and exercise counseling reduced the risk of T2DM by 58% (P <0.001). 35 Another study using diet and exercise showed reduced incidence of metabolic syndrome by 41% (P <0.001). 36 Several drugs have demonstrated favorable outcomes in preventing or delaying the onset of diabetes. Metformin, acarbose, and orlistat have shown positive trends in reducing the progression to T2DM (relative risk reduction, 31%, 25%, and 37%, respectively). [36][37][38] Thiazolidinediones have also shown beneficial effects on T2DM risk reduction. The Troglitazone in the Prevention of Diabetes (TRIPOD) trial showed reduced progression to diabetes (overall relative risk reduction, 56%, P = 0.02). 39 In this study, a small group of Hispanic women (n = 133) with a past history of gestational diabetes were randomized to treatment with troglitazone or placebo with a median follow-up of 30 months. As a follow-up study to TRIPOD, the Pioglitazone in the Prevention of Diabetes (PIPOD) trial also showed positive results. 40   tained the stability in β-cell function that occurred in those previously treated with troglitazone. Additionally, the incidence of developing T2DM (average rate of 4.6% per year) remained consistent with the results shown in TRIPOD. 40 In a recent large, multicenter clinical trial (n = 5,269), Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications (DREAM), a 62% decrease (P <0.001) in the development of T2DM in rosiglitazone-treated compared with placebo-treated patients was demonstrated. 41 This effect was not seen in ramipril-treated patients. There was a trend toward increased CV events in the rosiglitazone group; however, this was due to increased heart failure events in the rosiglitazone group compared with the placebo group (14 cases vs. 2 cases, respectively; P = 0.01). 41 The results of TRIPOD, PIPOD, and DREAM may suggest a potential class effect of slowing the progression to T2DM for TZDs. However, until additional information is available to support the cost-effectiveness of these interventions, the ADA does not recommend drug therapy for prevention of T2DM. 27 ss Effect of Peroxisome Proliferator-Activated

Receptor Agonists on Atherosclerosis
Emerging studies are beginning to show that peroxisome proliferator-activated receptor (PPAR) agonists, including the TZD subclass for treating diabetes, have unique properties that may reverse the progression of atherosclerosis. 42 PPARs regulate the expression of genes that control lipid metabolism and inhibit expression of proinflammatory genes. 43 The PPAR family comprises 3 types of receptors-alpha (α), gamma (γ), and delta (δ). These receptors are found in the major cell types (e.g., macrophages, smooth muscle cells, lymphocytes, and endothelial cells) that are located in atherosclerotic lesions. 43 Activation of PPAR-α increases HDL-C synthesis, stimulates reverse cholesterol transport, decreases TG levels, and stimulates fatty acid oxidation. When PPAR-γ is activated, insulin sensitization, glucose homeostasis, lipid metabolism, and adipocyte differentiation occur. 44 Researchers are studying the effects of PPAR-δ activation on fatty acid metabolism and obesity. Available drug therapy targeting PPARs include TZDs (PPAR-γ agonists) and fibrates (PPAR-α agonists). 45 Natural ligands for PPAR receptors include fatty acids and oxidized fatty acids. When the PPAR receptor is activated, there is a direct effect on vascular and inflammatory cells resulting in decreased cytokines, chemokines, and adhesion molecules and increased cholesterol efflux. Upon PPAR activation, there is also an indirect effect on adipose tissue, liver, and skeletal muscle that results in decreased FFA, glucose, and TG levels and increased insulin sensitivity and HDL-C levels. Both the direct and indirect effects reduce inflammation and diminish the progression of atherosclerosis. 46 Specific to TZDs, activation of the PPAR-γ receptor reduces insulin resistance, preserves pancreatic β-cell function, and may improve the CV risk profile by exerting positive effects on the dyslipidemia associated with T2DM. 45 In addition, there is a decrease in renal microalbumin excretion, blood pressure, and arterial wall adhesion molecules proliferation/migration, as well as a reduction in PAI-1, CRP, and FFA levels. Circulating adiponectin, an antiatherogenic adipokine, is increased. 47 Studies have shown that increased levels of adiponectin lead to improved insulin sensitivity and reduced risk of MI. 48,49 Additionally, studies have shown that metformin reduces PAI-1 levels in patients with T2DM. 50 Therefore, combined therapy with a TZD and metformin may have synergistic effects on reducing CV complications.

Cardiovascular Disease Risk Reduction
Patients with T2DM typically have several CV risk factors, which are listed in Table 3. 51 The main treatment goal is to decrease the incidence of CV morbidity and mortality by reducing or eliminating   Figure 3 demonstrates this relationship and shows that as the A1C approaches and exceeds 7%, the number of CHD events per 100 persons increases substantially. 52 There are several classes of agents that are used to decrease the risk of CV complications such as MI and stroke. Through blood pressure lowering and other positive effects, antihypertensive agents reduce CV complications. Studies have shown that antihypertensive therapy is associated with a 35% to 40% reduction in stroke incidence and a 20% to 25% reduction in MIs. 51 Because of renoprotective effects, ACE inhibitors and ARBs are often used as initial therapy in patients with diabetes. 51 The ADA blood pressure goal for patients with diabetes is <130/80 mm Hg. 51 Typically, patients with T2DM will require multiple agents to reach this goal. In addition, low-dose aspirin therapy, smoking cessation, and other lifestyle changes have proved beneficial. 27 Numerous studies with statins, fibrates, and other antihyperlipidemic agents have demonstrated the ability of these agents to reduce CV complications. [52][53][54][55][56] Patients with T2DM typically have mild to moderately increased LDL-C, elevated TG, and low HDL-C levels. The NCEP ATP III LDL-C goal for patients with diabetes is <100 mg/dL. If the TG level is >500 mg/dL, the TG level should be addressed before the LDL-C level is treated to avoid pancreatitis. 15 In addition, identification and treatment of the metabolic syndrome risk factors is recommended. Previously, low HDL-C was not considered a primary goal of treatment, but was treated by diet, exercise, and select lipid-lowering agents once the LDL-C  Metformin hydrochloride (Glucophage, Glucophage XR)

Mechanism of Action
Decreases hepatic glucose production Increases sensitivity of muscle, fat, and liver to exogenous insulin; activation of PPAR-γ receptor plays a role in glucose and lipid metabolism

Enhances insulin secretion
Stimulates insulin secretion (binds to different receptor than sulfonylurea)

Expected
Decrease in A1C (%)  goal had been met. 15,57 On the basis of clinical trials published since the release of the NCEP ATP III guidelines, revisions have been made to the treatment algorithm. For very high-risk patients (i.e., evidence of CVD), a more aggressive LDL-C goal of <70 mg/dL is recommended. 57 If the high-risk patient also has elevated TGs levels or low HDL-C levels, then addition of a fibrate or nicotinic acid should be considered. 15, 57 The revised treatment algorithm stresses the clinical importance of low HDL levels in any high or moderately high-risk person with lifestyle-related risk factors (e.g., obesity, physical inactivity, high TGs, low HDL-C, the metabolic syndrome). Regardless of their LDL-C level, these patients should be treated with therapeutic lifestyle changes. 57 A CHD working group (25 investigators with expertise in epidemiology, endocrinology, molecular biology, public health, lipid metabolism, cardiovascular medicine, and preventive cardiology) addressed the impact of low HDL-C levels as a risk factor for CVD. 58 This group concluded that by increasing HDL-C levels, the frequency of coronary artery disease (CAD) was reduced. 58 More specifically, studies have shown that for every 1 mg/dL increase in HDL-C level, the incidence of CAD is decreased 2% to 3%. 58 Recent evidence from a large matched retrospective cohort study (matched on HDL-C and TG levels, age, sex, and year of HDL-C and TG measurement) of patients who were treated with fibrates compared with patients who were not

Mechanism of Action
Slows the rate of polysaccharide digestion in the small intestine Injections, frequent dosing GI AEs, expensive, modest clinical experience

Role in Therapy
Useful for targeting postprandial hyperglycemia Use as adjunctive therapy in inadequately controlled patients using mealtime insulin (may be used with concurrent sulfonylurea agent and/or metformin) Use as monotherapy or as adjunct therapy for inadequately controlled patient using metformin or TZD Use as adjunct therapy for patient inadequately controlled with sulfonylurea or metformin using fibrates showed beneficial outcomes with increased HDL-C levels for fibrate-treated patients. The study showed that for every 5 mg/dL increase in HDL-C level, there was a 26% reduction in CVD risk. 59 Emerging evidence continues to show the antiatherosclerotic properties of HDL-C. 60 In addition to its pivotal role in reverse cholesterol transport, HDL-C enhances NO bioavailability and has potential anti-inflammatory, antithrombotic, antioxidant, and antiapoptotic properties. As a result of researchers improving their knowledge of factors that promote HDL-C levels and its function, new drug therapies (e.g., more potent PPAR agonists) are in development. 60 Since patients with T2DM often exhibit mixed dyslipidemia, multiple agents may be required to reach treatment goals. However, there is an increased risk of adverse drug events (ADEs) when higher doses are used and/or certain antihyperlipidemic agents are combined (e.g., rhabdomyolysis when combining statins and fibrates) are combined. TZDs may have beneficial effects on the T2DM lipid profile without increasing the risk of rhabdomyolysis. A few studies have evaluated the lipid-lowering effects of pioglitazone and rosiglitazone. Compared with rosiglitazone, pioglitazone has shown a more favorable effect on lipid profiles. 61 In a study that was specifically designed to compare lipid effects of the TZDs, pioglitazone demonstrated beneficial effects on TG, HDL-C, and LDL-C levels ( Table 4). 61 However, both pioglitazone and rosiglitazone produce larger, more buoyant LDL-C particles, which are less atherogenic than the small, dense LDL-C particles normally found in patients with diabetes. 61 As depicted in the drug therapy chart (Table 2), CV benefits have been achieved when certain T2DM agents have been used. In the United Kingdom Prospective Diabetes Study (UKPDS), overweight, metformin-treated patients (n=342) showed improved CV outcomes (39% reduction in MI; P = 0.01 and 30% reduction in all macrovascular diseases; P = 0.02). 62 In patients with type 1 diabetes, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group showed that intensive diabetes treatment with insulin had beneficial effects on CVD. 63 The primary outcome was defined as a CV event that required revascularization. Compared with conventional treatment, intensive treatment reduced the risk of any CVD by 42% (95% confidence interval [CI], 9%-63%; P = 0.02) and the risk of nonfatal MI, stroke, or death from CVD by 57% (95% CI, 12%-79%; P = 0.02). 63 More recently, studies with pioglitazone and rosiglitazone have shown improved CV outcomes. In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study, T2DM patients at high risk for fatal MI and stroke treated with pioglitazone experienced a reduction in the secondary endpoint (composite of all-cause mortality, MI, or stroke). 64 Study results suggested that compared with placebo-treated patients, pioglitazone-treated patients experienced a 16% reduction (P = 0.027) in the composite event rate of all-cause mortality, nonfatal MI  Adapted from reference 52. A1C = glycosylated hemoglobin; CHD = coronary heart disease; CVD = cardiovascular disease; T2DM = type 2 diabetes melliltus. (exluding silent MI), and stroke. Although the secondary endpoint was met, the composite primary endpoint, which included death from any cause, nonfatal MI, stroke, acute coronary syndrome, leg amputations, coronary revascularization, or leg revascularization, was not met. 64 A recent abstract from the EASD annual meeting showed positive lipid trends in a subanalysis of the PROactive trial, which evaluated the effects of pioglitazone on lipid profiles. Pioglitazone-treatment groups showed favorable effects on TG and HDL-C levels and the LDL-C/HDL-C ratio. 65 An additional subanalysis of the PROactive study showed that pioglitazone reduced the risk of secondary stroke in high-risk T2DM patients by 28% (P <0.05) compared with placebo. 66 In this subanalysis, 984 patients with a prior history of stroke were treated with pioglitazone or placebo. There was a 10.2% versus 5.6% reduction in stroke (hazard ratio, 0.53; 95% CI, 0.34-0.94; P=0.008) for pioglitazone versus placebo-treated patients, respectively. In a similar fashion, the Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR), an ongoing substudy of the DREAM trial, is evaluating whether the combination of rosiglitazone and ramipril can induce regression of atherosclerosis. Carotid ultrasound will be used to evaluate the change in the mean carotid artery intima-media thickness (CIMT) and analyze the progression of atherosclerosis. This study is scheduled for completion in the second quarter of 2007. 67 Recently published, the Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO study), is a randomized controlled multicenter trial in patients with T2DM. 68 Patients (n=462) were newly diagnosed and currently treated with diet and exercise, sulfonylurea, metformin, insulin, or any combination of these. In addition to current therapy, patients received  Veterans Affairs Diabetes Trial (VADT) Rosiglitazone Metformin either pioglitazone or glimepiride. Measurement of CIMT was chosen as the primary outcome because CIMT is a marker of atherosclerosis and independently predicts CV events. At the end of the study period (week 72), progression of mean CIMT was less with pioglitazone compared with glimepiride (-0.001 mm vs. +0.012 mm; 95% CI, -0.024 to -0.002; P = 0.02). 68 Other benefits of pioglitazone included increased HDL-C levels and reduced TG levels. ADEs leading to study discontinuation occurred 11.3% for pioglitazone-treated patients versus 8.3% for glimepiride-treated patients. 68 Hypoglycemia was slightly more common with glimepiride-treated patients, while pioglitazone-treated patients more commonly experienced peripheral edema and weight gain. 68 There was 1 case of new congestive heart failure in the pioglitazone treatment group. 68 The results of the CHICAGO study combined with the results of the PROactive trial and its substudies indicate that certain subsets of patients may experience CV benefits when treated with pioglitazone. 64,66,68 Several ongoing and new trials are evaluating TZD and CV risk reduction (Table 5). 67 On the basis of the results of these trials, changes in the treatment of patients with T2DM or prediabetes may occur.

s ss s Emerging and Future Drug Therapy
In addition to the current treatments available for patients with T2DM and the potential new therapeutic effects of existing therapy (e.g., reducing CV risk), there are several emerging and future therapy options. Incretin mimetics/enhancers include GLP-1 receptor agonists, GLP-1 analogs, and DPP-IV inhibitors. Incretin hormones, secreted from the gastrointestinal tract in response to nutrient ingestion, aid in the overall maintenance of glucose homeostasis. 69 More specifically, release of GLP-1 stimulates glucose-dependent insulin secretion, inhibits release of glucagon, slows gastric emptying, and reduces food intake (due to promotion of satiety). 70,71 Since GLP-1 is reduced in patients with impaired glucose tolerance and T2DM, agents that mimic the actions of incretin hormones may be beneficial therapeutic options.
Exenatide, a GLP-1 receptor agonist (exendin analog), mimics the action of the incretin GLP-1, resulting in enhanced glucosedependent insulin secretion by pancreatic β-cells. Additionally, exenatide suppresses inappropriately elevated glucagon secretion and slows gastric emptying. Exenatide, an injectable agent for patients with T2DM, is indicated as adjunctive therapy for T2DM patients who have not achieved glycemic control and are taking metformin, a sulfonylurea, or metformin in combination with a sulfonylurea. 32 The U.S. Food and Drug Administration (FDA) recently approved sitagliptin, a DPP-IV inhibitor. DPP-IV is present in many tissues and affects numerous body proteins. Of importance in T2DM, DPP-IV rapidly breaks down the incretin hormones GLP-1 and gastric inhibitory polypeptide. DPP-IV inhibitors affect the overall maintenance of glucose metabolism by inhibiting the degradation of GLP-1. 31, 71 Sitagliptin, an oral agent for patients with T2DM, is indicated for use as monotherapy or in combina-tion with metformin or a TZD when adequate glycemic control has not been achieved. 31 Clinical data for vildagliptin, a second DPP-IV inhibitor, has been submitted to the FDA for approval. 72,73 Recently, new clinical data supporting the efficacy of vildagliptin was presented at the World Diabetes Congress of the IDF. 74 This agent may be available to the market during the second quarter of 2007. Additionally, several other DPP-IV inhibitors are in various stages of development. 75 After clinical experience with DPP-IV inhibitors is gained, their role in treating patients with T2DM will be better established.
Several GLP-1 analogs are currently in development. Liraglutide, an injectable, long-acting DPP-IV-resistant GLP-1 analog, is in phase III clinical trials. Initial studies of liraglutide monotherapy and in combination with metformin have shown improved glycemic control and weight loss. 76 Dual α/γ PPAR agonists (e.g., muraglitazar, tesiglitazar) looked promising for the treatment of T2DM because they improved insulin resistance and alleviated atherogenic lipidemia. However, clinical trials with muraglitzar, tesiglitazar, and other dual agonists have been discontinued due to increased risk of cardiotoxicity. 77 The discovery of a third type of PPAR receptor, PPAR-δ, may become a better target for drug therapy. PPAR-δ appears to play a central role in energy metabolism and may counterbalance the negative effects of dual alpha/gamma PPAR agonists. 78 Compounds targeting individual PPARs and all 3 PPARs (pan-PPAR agonists) are in various stages of development for T2DM, obesity, the metabolic syndrome, and dyslipidemia.
Rimonabant, a selective cannabinoid type 1 receptor blocker that suppresses the endocannabinoid system centrally and peripherally, has received an approvable letter from the FDA for treatment of obesity. The endocannabinoid system is a neuromodulatory system that plays a role in the regulation of food intake and energy homeostasis. 79 Rimonabant has positive effects on reducing caloric intake, hyperglycemia, and HDL-C and TG levels. Furthermore, some of these effects occur independent of weight loss. It is postulated that rimonabant enhances mRNA expression of adiponectin, which has antiatherogenic properties. [79][80][81] Clinical studies have shown that rimonabant is effective in the treatment of overweight or obese patients with T2DM. 80 Rimonabant-treated patients experienced weight loss (2.3 kg-5.3 kg) and improved glycemic and blood pressure control. Additionally, rimonabant-treated patients experienced improvements in atherogenic dyslipidemia and reduced prevalence of the metabolic syndrome. In a large randomized trial that evaluated rimonabant plus diet and exercise compared with placebo, rimonabant-treated patients experienced more weight loss; decreased waist circumference, lower TG levels, and higher HDL-C levels. 79

s ss s Use and Cost Considerations
Cardiovascular complications are a major component of T2DM that contribute significantly to the costs of managing diabetes. Therefore, it is important to not only treat hyperglycemia but also to identify treatment plans and antidiabetic agents that may improve CVD outcomes. Global risk reduction via multifactorial management and treatment of underlying risk factors is recommended. Lifestyle changes should be an ongoing intervention for all patients with T2DM. Weight loss will help reduce insulin resistance, LDL-C levels, and blood pressure. In addition, increased physical activity will facilitate weight loss; decrease blood pressure, VLDL-C (very low-density lipoprotein cholesterol), and LDL-C levels; and increase HDL-C levels. Patients should be provided with specific diet and exercise recommendations and referred to a dietician when necessary.
For successful treatment, it is vitally important for the patient to actively participate in the treatment plan. There are several choices for drug therapy. If there are no contraindications, including renal disease (SCr >1.5 mg/dL) for males and >1.4 mg/dL for females), heart failure requiring pharmacologic treatment, or acute or chronic metabolic acidosis, then metformin should be initiated first. 29 Metformin is one of the most cost-effective treatments for T2DM, and on the basis of the UKPDS, patients may experience beneficial CV outcomes and weight loss when treated with this agent. If the patient does not reach his or her glycemic goal with the initial dose, metformin can be titrated to the maximum dose or a second agent may be added.
Since most patients with T2DM have the metabolic syndrome and are likely to experience insulin resistance, a TZD may be an appropriate treatment option. Additionally, TZDs may have other advantages as suggested by the PROactive, CHICAGO, and DREAM trials. 41,66,68 However, the use of TZDs may cause weight gain and fluid retention, which may lead to an increased risk of heart failure. TZDs are not indicated for patients with liver disease or New York Heart Association (NYHA) grade III or IV heart failure. 82,83 While the labeling has not been updated, the package insert for rosiglitazone has been updated to include precautions for use in patients with NYHA grade I or II heart failure. 82 A consensus statement from the American Heart Association and the ADA cautions about the use of TZDs in patients with heart failure. 84 Specific risk factors and appropriate use and monitoring recommendations are provided in the statement.
A recent critical review discussed whether the use of TZDs lead to heart failure. 85 Studies have shown that the incidence of fluid retention is approximately 5%, 4% to 7%, and 15% when used as monotherapy, concomitantly with metformin or sulfonylurea, and concomitantly with insulin, respectively. 85 However, the risk of developing heart failure seems less clear. The incidence of heart failure reported in clinical trials with TZDs is less than 1% and appears to be associated with underlying dysfunction. 85 Furthermore, evidence suggests that compared with sulfonlyureas, TZDs do not cause statistically significant alterations in left ventricular mass index and ejection fraction. 86 When considering TZDs, conditions (e.g., previous MI or valvular disease) that might predispose the patient to developing heart failure should be evaluated. Also, concomitant medications (e.g., vasodilators, nonsteroidal anti-inflammatory drugs, glucocorticoids, and herbal drugs containing licorice) that may contribute to fluid retention should be identified. [85][86][87] All patients should be monitored for new pedal edema, weight gain of more than 3 kg, dyspnea, or fatigue. 85 Appropriate patient selection, titration, patient education, and monitoring can help minimize ADEs associated with the use of TZDs.
As part of an ongoing treatment plan, patients should be reeducated about their disease and treatment and monitored frequently for effectiveness of therapy and potential ADEs. It is also important to evaluate patient adherence on a regular basis. Pharmacists can play an important role when assessing patients and helping to improve adherence. A recent study evaluated the effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Nonadherent patients had higher A1C, systolic and diastolic blood pressure, and LDL-C levels. Consequently, nonadherent patients had higher all-cause hospitalization (23.2% vs. 19.2%, P <0.001) and higher all-cause mortality (5.9% vs. 4.0%, P <0.001). 88 Nonadherence may be improved by providing appropriate patient education; by involving patients in their treatment plans; and by providing medications that allow for less frequent dosing, ease of administration, and improved tolerability. A study evaluating the long-term safety of pioglitazone versus glyburide suggested that patients who were treated with pioglitazone were less likely to discontinue treatment because of lack of efficacy or ADEs (12.8% vs. 20.8%; P = 0.032). 89 There is not an abundance of literature that specifically evaluates the cost-effectiveness of treating patients with antidiabetic agents to reduce CVD complications. Factors to consider include the costs associated with standard office visits, drug therapy, and monitoring compared with the costs of treating complications, which are often due to CVD and require emergency room visits, hospitalizations, and more intensive treatment. A utilization study found that adding rosiglitazone in combination with sufonlyurea therapy decreased the use of medical resources such as hospitalizations and emergency room visits. 90 Cost estimates from 2002 associated with diabetes were $132 billion per year. On the basis of the current prevalence of T2DM and projected population growth from the U.S. Census Bureau, this number is expected to increase to $156 billion by 2010 and to $196 billion by 2020. 5 If the incidence of T2DM continues to rise exponentially due to the increasing number of obese persons, these costs could become substantially higher. Furthermore, when evaluating costs for inpatient care days, nursing home care days, and outpatient care (including physician office, emergency, hospital outpatient, home health, and hospice care visits), researchers find that treatment of patients with CVD is associated with the highest costs compared with all other T2DM complications. 5 To decrease CVD morbidity and mortality, all treatments options (e.g., lifestyle Type 2 Diabetes and Cardiovascular Disease: Reducing the Risk changes, metformin, TZDs, statins, fibrates, ACE inhibitors, ARBs, low-dose aspirin therapy) that have been shown to reduce CV risk factors and improve CVD outcomes should be considered and used when appropriate. s ss s Conclusions T2DM has reached epidemic proportions, resulting in increased morbidity and mortality due to CVD. In fact, on the basis of the 2006 data from the IDF, the global prevalence of T2DM has continued to increase at a rapid pace. Studies have shown the impact of obesity and T2DM on the progression of atherosclerosis and CVD. T2DM has become a major burden on the U.S. health care system. Because of the rising population of obese persons resulting in increased prevalence of T2DM, the costs associated with T2DM will continue to rise at exorbitant rates if drastic changes do not occur. The majority of costs associated with T2DM are due to CV complications, with most of these costs occurring within the first 10 years after the patient is diagnosed with T2DM. 6 Therefore, with early and aggressive treatment plans for controlling T2DM, health care costs associated with managing CVD events can be minimized. Patients with prediabetes, i.e., those with impaired fasting glucose or impaired glucose tolerance, should be educated about the importance of lifestyle interventions. All patients should be routinely educated about their disease and instructed about lifestyle changes such as diet, exercise, and smoking cessation. Pharmacists have the opportunity to play a vital role on the health care team by educating patients about the benefits of their treatment plans, monitoring for adherence to therapy and for ADEs, and recommending additional therapy when appropriate.
There are many treatment options for patients with T2DM. Drug therapy that is safe and effective, tolerable, and acceptable to the patient should be selected. Other important goals include selecting agents that can provide maximum benefit to the patient by affecting more than one metabolic disturbance, decreasing overall treatment costs, and improving the patient' s quality of life by reducing morbidity associated with CVD. Agents, including TZDs, statins, fibrates, aspirin, ACE inhibitors, and ARBs that have been shown to demonstrate beneficial CV outcomes in patients with T2DM, should be considered standard treatment options. In summary, initiating early and aggressive treatment that includes lifestyle changes and multiple agents with proven abilities to reduce the risk of CVD will provide the greatest benefit when managing patients with T2DM.

ACKNOWLEDGMENT
The authors thank Penny DeFalco, PharmD, Naperville, Illinois, for her assistance in writing and editing this article.

DISCLOSURES
This article is based on a presentation given by the authors at a symposium, "Type 2 Diabetes and Cardiovascular Disease: Reducing the Risk," held October 4, 2006, at the time of the Academy of Managed Care Pharmacy' s 2006 Educational Conference in Chicago, Illinois. The symposium was supported by an educational grant from Takeda Pharmaceuticals North America, Inc. and was sponsored by ProCE, Inc. The authors disclose that they have received honoraria from ProCE, Inc. for participation in the symposium and this supplement.
Author David W. Bartels discloses the following commercial/financial relationships through grant/research support, consultant services, and/or speakers bureau: Lilly, Pfizer, sanofi-aventis, and Takeda. Author Michael H. Davidson discloses the following commercial/financial relationships through grant/ research support, consultant services, and/or speakers bureau: Abbott, AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, Roche, Sankyo, Sumitomo, and Takeda. Author William C. Gong discloses that he has no direct financial relationships to report.
Bartels served as principal author of the study. Study concept and design were contributed by all authors.